KR100377855B1 - 아미노산 히드록시에틸아미노 술폰아미드 레트로바이러스 프로테아제 저해제 - Google Patents

Info

Publication number

KR100377855B1

KR100377855B1 KR1019970706313A KR19970706313A KR100377855B1 KR 100377855 B1 KR100377855 B1 KR 100377855B1 KR 1019970706313 A KR1019970706313 A KR 1019970706313A KR 19970706313 A KR19970706313 A KR 19970706313A KR 100377855 B1 KR100377855 B1 KR 100377855B1

Authority

KR

South Korea

Prior art keywords

amino

radical

propyl

phenylmethyl

carbon atoms

Prior art date

1995-03-10

Links

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• 230000001177 retroviral effect Effects 0.000 title claims abstract description 24
• 239000000137 peptide hydrolase inhibitor Substances 0.000 title abstract description 10
• 150000001413 amino acids Chemical class 0.000 title description 11
• 229940124158 Protease/peptidase inhibitor Drugs 0.000 title description 3
• JKTOKCJLZBURKJ-UHFFFAOYSA-N 1-hydroxy-2-(sulfamoylamino)ethane Chemical compound NS(=O)(=O)NCCO JKTOKCJLZBURKJ-UHFFFAOYSA-N 0.000 title 1
• -1 amino acid hydroxyethylaminosulfonamide compounds Chemical class 0.000 claims abstract description 458
• 239000000203 mixture Substances 0.000 claims abstract description 148
• 150000001875 compounds Chemical class 0.000 claims abstract description 106
• 238000000034 method Methods 0.000 claims abstract description 92
• 108091005804 Peptidases Proteins 0.000 claims abstract description 21
• 239000004365 Protease Substances 0.000 claims abstract description 20
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 11
• 241001430294 unidentified retrovirus Species 0.000 claims abstract description 8
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 6
• 206010038997 Retroviral infections Diseases 0.000 claims abstract description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 350
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 210
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 196
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 162
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 115
• 125000004432 carbon atom Chemical group C* 0.000 claims description 76
• 229910052757 nitrogen Inorganic materials 0.000 claims description 59
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 150000003254 radicals Chemical class 0.000 claims description 47
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
• 239000001257 hydrogen Substances 0.000 claims description 45
• 125000000217 alkyl group Chemical group 0.000 claims description 43
• 150000003839 salts Chemical class 0.000 claims description 41
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 26
• 150000002431 hydrogen Chemical class 0.000 claims description 25
• 125000003118 aryl group Chemical group 0.000 claims description 20
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 19
• 150000002148 esters Chemical class 0.000 claims description 18
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 17
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 15
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• 229910052805 deuterium Inorganic materials 0.000 claims description 11
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 10
• YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 9
• 229940002612 prodrug Drugs 0.000 claims description 9
• 239000000651 prodrug Substances 0.000 claims description 9
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 125000003545 alkoxy group Chemical group 0.000 claims description 7
• 150000001721 carbon Chemical group 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 7
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 125000004540 benzothiazol-5-yl group Chemical group S1C=NC2=C1C=CC(=C2)* 0.000 claims description 6
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• 125000001424 substituent group Chemical group 0.000 claims description 6
• 150000003457 sulfones Chemical class 0.000 claims description 6
• 150000003462 sulfoxides Chemical class 0.000 claims description 6
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 230000010076 replication Effects 0.000 claims description 5
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
• KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 4
• 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 4
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
• AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
• 125000005164 aryl thioalkyl group Chemical group 0.000 claims description 3
• 125000004533 benzofuran-5-yl group Chemical group O1C=CC2=C1C=CC(=C2)* 0.000 claims description 3
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 3
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000003884 phenylalkyl group Chemical group 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 3
• 208000030507 AIDS Diseases 0.000 claims description 2
• 125000005002 aryl methyl group Chemical group 0.000 claims description 2
• HXCKCCRKGXHOBK-UHFFFAOYSA-N cycloheptane Chemical compound [CH]1CCCCCC1 HXCKCCRKGXHOBK-UHFFFAOYSA-N 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
• GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
• VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 claims 2
• 229910019142 PO4 Inorganic materials 0.000 claims 1
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
• 125000004429 atom Chemical group 0.000 claims 1
• 125000004981 cycloalkylmethyl group Chemical group 0.000 claims 1
• 238000000338 in vitro Methods 0.000 claims 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
• 239000010452 phosphate Substances 0.000 claims 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims 1
• 241000725303 Human immunodeficiency virus Species 0.000 abstract description 11
• 238000011282 treatment Methods 0.000 abstract description 11
• 102000035195 Peptidases Human genes 0.000 abstract description 10
• 239000003112 inhibitor Substances 0.000 abstract description 10
• 108010010369 HIV Protease Proteins 0.000 abstract description 6
• 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 abstract description 6
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 421
• 239000000243 solution Substances 0.000 description 228
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 186
• 235000019439 ethyl acetate Nutrition 0.000 description 142
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 132
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 115
• 239000000047 product Substances 0.000 description 95
• 238000002360 preparation method Methods 0.000 description 94
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 85
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 75
• 239000002904 solvent Substances 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 75
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 74
• 238000006243 chemical reaction Methods 0.000 description 70
• 239000007787 solid Substances 0.000 description 70
• 239000012267 brine Substances 0.000 description 64
• 230000002829 reductive effect Effects 0.000 description 64
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 64
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 59
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 57
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 53
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 53
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
• 239000011541 reaction mixture Substances 0.000 description 45
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 37
• 235000019341 magnesium sulphate Nutrition 0.000 description 37
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 36
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 36
• 239000012044 organic layer Substances 0.000 description 33
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 32
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
• 239000012043 crude product Substances 0.000 description 32
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 31
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 27
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
• 229920006395 saturated elastomer Polymers 0.000 description 27
• 239000010410 layer Substances 0.000 description 26
• 239000003921 oil Substances 0.000 description 26
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 25
• 239000000741 silica gel Substances 0.000 description 25
• 229910002027 silica gel Inorganic materials 0.000 description 25
• 238000003756 stirring Methods 0.000 description 25
• 239000002253 acid Substances 0.000 description 23
• 239000003054 catalyst Substances 0.000 description 23
• 238000001914 filtration Methods 0.000 description 23
• 150000001412 amines Chemical class 0.000 description 22
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
• 238000004128 high performance liquid chromatography Methods 0.000 description 21
• 238000000746 purification Methods 0.000 description 21
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
• 229940024606 amino acid Drugs 0.000 description 20
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Chemical group O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 20
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 18
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
• 235000001014 amino acid Nutrition 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 18
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 17
• LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
• 238000010992 reflux Methods 0.000 description 16
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical group C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 15
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 15
• 150000001299 aldehydes Chemical class 0.000 description 15
• COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 14
• 239000003153 chemical reaction reagent Substances 0.000 description 14
• 229910052698 phosphorus Inorganic materials 0.000 description 14
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
• KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• PJGJQVRXEUVAFT-UHFFFAOYSA-N chloroiodomethane Chemical compound ClCI PJGJQVRXEUVAFT-UHFFFAOYSA-N 0.000 description 13
• KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 13
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 12
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 12
• JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 12
• FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 12
• 229940106681 chloroacetic acid Drugs 0.000 description 12
• 239000007858 starting material Substances 0.000 description 12
• 239000000725 suspension Substances 0.000 description 12
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
• 0 CC1=CCC2N=C(*)*C2=*1 Chemical compound CC1=CCC2N=C(*)*C2=*1 0.000 description 11
• 239000002585 base Substances 0.000 description 11
• 239000000460 chlorine Substances 0.000 description 11
• 238000002844 melting Methods 0.000 description 11
• 230000008018 melting Effects 0.000 description 11
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 11
• 239000000843 powder Substances 0.000 description 11
• 125000006239 protecting group Chemical group 0.000 description 11
• 238000012360 testing method Methods 0.000 description 11
• 238000004458 analytical method Methods 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 239000006260 foam Substances 0.000 description 10
• 239000000543 intermediate Substances 0.000 description 10
• 239000012299 nitrogen atmosphere Substances 0.000 description 10
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 10
• 150000002924 oxiranes Chemical class 0.000 description 10
• 229910052763 palladium Inorganic materials 0.000 description 10
• 229960005190 phenylalanine Drugs 0.000 description 10
• 238000010898 silica gel chromatography Methods 0.000 description 10
• KDSNLYIMUZNERS-UHFFFAOYSA-N 2-methylpropanamine Chemical compound CC(C)CN KDSNLYIMUZNERS-UHFFFAOYSA-N 0.000 description 9
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 9
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
• 241000700605 Viruses Species 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 125000000753 cycloalkyl group Chemical group 0.000 description 9
• 235000019419 proteases Nutrition 0.000 description 9
• 235000018102 proteins Nutrition 0.000 description 9
• 108090000623 proteins and genes Proteins 0.000 description 9
• 102000004169 proteins and genes Human genes 0.000 description 9
• 239000011734 sodium Substances 0.000 description 9
• 102000004190 Enzymes Human genes 0.000 description 8
• 108090000790 Enzymes Proteins 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 8
• 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 8
• 238000004519 manufacturing process Methods 0.000 description 8
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
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